Department of Pharmacology and Toxicology, College of Osteopathic Medicine, East Lansing, MI 48824, USA.
Medicinal Chemistry Facility, Michigan State University, East Lansing, MI 48824, USA.
Int J Mol Sci. 2023 Feb 21;24(5):4298. doi: 10.3390/ijms24054298.
Retinoid X receptor (RXR) agonists, which activate the RXR nuclear receptor, are effective in multiple preclinical cancer models for both treatment and prevention. While RXR is the direct target of these compounds, the downstream changes in gene expression differ between compounds. RNA sequencing was used to elucidate the effects of the novel RXRα agonist MSU-42011 on the transcriptome in mammary tumors of HER2+ mouse mammary tumor virus (MMTV)-Neu mice. For comparison, mammary tumors treated with the FDA approved RXR agonist bexarotene were also analyzed. Each treatment differentially regulated cancer-relevant gene categories, including focal adhesion, extracellular matrix, and immune pathways. The most prominent genes altered by RXR agonists positively correlate with survival in breast cancer patients. While MSU-42011 and bexarotene act on many common pathways, these experiments highlight the differences in gene expression between these two RXR agonists. MSU-42011 targets immune regulatory and biosynthetic pathways, while bexarotene acts on several proteoglycan and matrix metalloproteinase pathways. Exploration of these differential effects on gene transcription may lead to an increased understanding of the complex biology behind RXR agonists and how the activities of this diverse class of compounds can be utilized to treat cancer.
维甲酸 X 受体 (RXR) 激动剂激活 RXR 核受体，在多种临床前癌症模型中对治疗和预防均有效。虽然 RXR 是这些化合物的直接靶点，但不同化合物之间下游的基因表达变化不同。使用 RNA 测序来阐明新型 RXRα 激动剂 MSU-42011 对 HER2+ 鼠乳腺肿瘤病毒 (MMTV)-Neu 小鼠乳腺肿瘤转录组的影响。为了进行比较，还分析了经 FDA 批准的 RXR 激动剂贝沙罗汀治疗的乳腺肿瘤。每种治疗都以不同的方式调节与癌症相关的基因类别，包括黏附斑、细胞外基质和免疫途径。RXR 激动剂改变最显著的基因与乳腺癌患者的生存呈正相关。虽然 MSU-42011 和贝沙罗汀作用于许多共同的途径，但这些实验突出了这两种 RXR 激动剂之间在基因表达上的差异。MSU-42011 靶向免疫调节和生物合成途径，而贝沙罗汀作用于几种蛋白聚糖和基质金属蛋白酶途径。对基因转录这些差异作用的探索可能会增加对 RXR 激动剂背后复杂生物学的理解，以及如何利用这一类多样化的化合物来治疗癌症。
